Considerable advances have been made in breast cancer epidemiology, yet the disease remains the most commonly diagnosed cancer in US women and difficult to prevent. Therefore, it is imperative to pursue the discovery of potential new modifiable risk factors. Multiple lines of evidence suggest that cadmium, a widespread and persistent heavy metal environmental pollutant, is a carcinogen in breast tissue, but more definitive epidemiological investigation is required. In spite of the known carcinogenic risks associated with very high levels of cadmium exposure that occur in industrial settings, little is known about the carcinogenicity of low levels of cadmium exposure over a lifetime. Both in vitro and animal experiments show that cadmium has estrogenic properties, making cadmium a plausible risk factor for estrogen dependent tumors such as breast cancer. In a previous retrospective case#control study we found a more than two#fold increase in breast cancer risk associated with high urine cadmium, a result supported by a second recent similar study. We now propose to perform a more definitive test of this hypothesis within the Women's Health Initiative (WHI), a prospective cohort study of preventive health practices in postmenopausal women. First, we will assess cadmium exposure through measurement of urine cadmium. Approximately 10,000 participants in the WHI donated urine at enrollment, and 567 incident cases of invasive breast cancer were documented in these women through August 2010. We plan to evaluate the association between urine cadmium and breast cancer risk in a nested case#control study, matching these breast cancer cases with approximately 1,000 controls. Second, we will use established methods to calculate dietary exposure to cadmium among all ~161,000 WHI participants-including ~7,000 women diagnosed with invasive breast cancer-who completed food frequency questionnaires and estimate the hazard of invasive breast cancer associated with dietary cadmium exposure. Finally, for both of these aims we will examine associations in hormonally#defined subgroups to learn more about the mechanisms whereby cadmium may be associated with breast cancer risk. Because most women are exposed to cadmium through the consumption of foods grown in contaminated soils and through cigarette smoke, strategies that reduce cadmium pollution may present opportunities for reducing breast cancer incidence. The efficient and powerful design of the proposed study will provide timely new information on the contribution of a ubiquitous environmental contaminant to the incidence of invasive breast cancer. PUBLIC HEALTH RELEVANCE: Breast cancer is the most common cancer diagnosed in US women. Promising leads on modifiable risk factors, including environmental chemicals, should be investigated because of the potential for new prevention strategies. Cadmium is a ubiquitous environmental contaminant that preliminary evidence shows may be associated with breast cancer, possibly through its estrogenic effects. We will efficiently test this hypothesis in the prospective Women's Health Initiative cohort, using previously collected WHI bio-specimens and data, state-of-the-art cadmium assays and epidemiologic analysis. This study will be an important step toward a fuller understanding of the preventable causes of breast cancer.